Tu Kangsheng, Liu Zhikui, Yao Bowen, Han Shaoshan, Yang Wei
Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Int J Oncol. 2016 Mar;48(3):965-74. doi: 10.3892/ijo.2015.3309. Epub 2015 Dec 28.
MicroRNAs (miRNAs) have been found to play fundamental roles in the pathogenesis of hepatocellular carcinoma (HCC). Previous miRNA array data showed that miR-519a was upregulated in HCC tissues compared to adjacent non-tumor tissues. However, the functional role of miR-519a in HCC remains unexplored. In this study, we demonstrated that the expression of miR-519a was elevated in both HCC tissues and cell lines. Clinical association analysis revealed that high expression of miR-519a was correlated with adverse clinicopathological characteristics including large tumor size, high Edmondson-Steiner grading, advanced tumor-node-metastasis (TNM) tumor stage and venous infiltration. Furthermore, high expression of miR-519a conferred a reduced 5-year overall survival and disease-free survival of HCC patients. Moreover, we disclosed that miR-519a overexpression promoted, but miR-519a silencing reduced, HCC cell proliferation and cell cycle progression in vitro. Notably, we identified phosphatase and tensin homolog (PTEN) as a direct downstream target and functional mediator of miR-519a in HCC cells. Mechanistically, phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway, downstream of PTEN, is essential for the functional roles of miR-519a in HCC cells. In conclusion, our results indicate that miR-519a promotes tumor growth of HCC by targeting PTEN-mediated PI3K/AKT pathway, and potentially serves as a novel prognostic biomarker and therapeutic target for HCC.
微小RNA（miRNA）已被发现在肝细胞癌（HCC）的发病机制中发挥重要作用。先前的miRNA阵列数据显示，与相邻的非肿瘤组织相比，miR-519a在HCC组织中表达上调。然而，miR-519a在HCC中的功能作用仍未被探索。在本研究中，我们证明miR-519a在HCC组织和细胞系中均表达升高。临床关联分析显示，miR-519a的高表达与不良的临床病理特征相关，包括肿瘤体积大、Edmondson-Steiner分级高、肿瘤-淋巴结-转移（TNM）分期晚和静脉浸润。此外，miR-519a的高表达导致HCC患者5年总生存率和无病生存率降低。此外，我们发现miR-519a过表达促进，但miR-519a沉默减少，体外HCC细胞增殖和细胞周期进程。值得注意的是，我们确定磷酸酶和张力蛋白同源物（PTEN）是HCC细胞中miR-519a的直接下游靶点和功能介质。机制上，PTEN下游的磷脂酰肌醇-3-羟基激酶（PI3K）/AKT通路对于miR-519a在HCC细胞中的功能作用至关重要。总之，我们的结果表明，miR-519a通过靶向PTEN介导的PI3K/AKT通路促进HCC肿瘤生长，并可能作为HCC的一种新的预后生物标志物和治疗靶点。
